Nguyen Van, Hawkins Cynthia, Bergeron Catherine, Supala Agnes, Huang Jean, Westaway David, St George-Hyslop Peter, Rozmahel Richard
Dept. of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
Brain Res. 2006 May 1;1086(1):76-84. doi: 10.1016/j.brainres.2006.02.122. Epub 2006 Apr 13.
Nicastrin is a member of the high molecular weight presenilin complex that plays a central role in gamma-secretase cleavage of numerous type-1 membrane-associated proteins required for cell signaling, proliferation and lineage development. We have generated a nicastrin-null mouse line by disruption of exon 3. Similar to previously described nicastrin-null mice, these animals demonstrate severe growth retardation, mortality beginning at embryonic age 10.5 days, and marked developmental abnormalities indicative of a severe Notch phenotype. Preceding their mortality, 10.5-day-old nicastrin-null embryos were found to also exhibit specific apoptosis within regions showing profound deformities, particularly in the developing heart and brain. This result suggests that complete disruption of presenilin complexes elicits programmed cell death, in addition to a Notch phenotype, which may contribute to the developmental abnormalities and embryonic mortality of nicastrin-null mice and possibly neurodegeneration in Alzheimer's disease.
尼卡斯特林是高分子量早老素复合物的成员，该复合物在γ-分泌酶切割众多细胞信号传导、增殖和谱系发育所需的1型膜相关蛋白过程中起核心作用。我们通过破坏外显子3生成了尼卡斯特林基因敲除小鼠品系。与先前描述的尼卡斯特林基因敲除小鼠相似，这些动物表现出严重的生长迟缓，从胚胎期10.5天开始死亡，并有明显的发育异常，表明存在严重的Notch表型。在它们死亡之前，发现10.5天大的尼卡斯特林基因敲除胚胎在显示出严重畸形的区域，特别是在发育中的心脏和大脑中，也表现出特定的细胞凋亡。这一结果表明，早老素复合物的完全破坏除了引发Notch表型外，还会引发程序性细胞死亡，这可能导致尼卡斯特林基因敲除小鼠的发育异常和胚胎死亡，并可能与阿尔茨海默病中的神经退行性变有关。
